Generic placeholder image

Letters in Drug Design & Discovery

Editor-in-Chief

ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Computational Analysis of Dynamical Fluctuations of Oncoprotein E7 (HPV 16) for the Hot Spot Residue Identification Using Elastic Network Model

Author(s): Rabbiah Malik*, Sahar Fazal and Mohammad Amjad Kamal

Volume 17, Issue 11, 2020

Page: [1393 - 1400] Pages: 8

DOI: 10.2174/1570180817999200606225735

Price: $65

Abstract

Aims: To find out Potential Drug targets against HPV E7.

Background: Oncoprotein E7 of Human Papilloma Virus (HPV-16), after invading human body alter host protein-protein interaction networks caused by the fluctuations of amino acid residues present in E7. E7 interacts with Rb protein of human host with variable residual fluctuations, leading towards the progression of cervical cancer.

Objective: Our study was focused our computational analysis of the binding and competing interactions of the E7 protein of HPV with Rb protein.

Methods: Our study is based on analysis of dynamic fluctuations of E7 in host cell and correlation analysis of specific residue found in motif of LxCxE, that is the key region in stabilizing interaction between E7 and Rb.

Results and Discussions: Cysteine, Leucine and Glutamic acid have been identified as hot spot residues of E7 which can provide platform for drug designing and understanding of pathogenesis of cervical cancer, in future. Our study shows validation of the vitality of linear binding motifs LxCxE of E7 of HPV in interacting with Rb as an important event in propagation of HPV in human cells and transformation of infection into cervical cancer.

Conclusion: Our study shows validation of the vitality of linear binding motifs LxCxE of E7 of HPV in interacting with Rb as an important event in propagation of HPV in human cells and transformation of infection into cervical cancer.

Other: E7 interacts with Rb protein of human host with variable residual fluctuations, leading towards the progression of cervical cancer.

Keywords: E7, ENM, HPV E7, dynamic fluctuations, drug targets, B-factors, hot spots residues.

Graphical Abstract

[1]
Tournier, J.N.; Quesnel-Hellmann, A. Host-pathogen interactions: a biological rendez-vous of the infectious nonself and danger models? PLoS Pathog., 2006, 2(5)e44
[http://dx.doi.org/10.1371/journal.ppat.0020044] [PMID: 16733542]
[2]
Sodhi, A.; Montaner, S.; Gutkind, J.S. Viral hijacking of G-protein-coupled-receptor signalling networks. Nat. Rev. Mol. Cell Biol., 2004, 5(12), 998-1012.
[http://dx.doi.org/10.1038/nrm1529] [PMID: 15573137]
[3]
Dampier, W.; Tozeren, A. Signaling perturbations induced by invading H. pylori proteins in the host epithelial cells: a mathematical modeling approach. J. Theor. Biol., 2007, 248(1), 130-144.
[http://dx.doi.org/10.1016/j.jtbi.2007.03.014] [PMID: 17559886]
[4]
Roeth, J.F.; Collins, K.L. Human immunodeficiency virus type 1 Nef: adapting to intracellular trafficking pathways. Microbiol. Mol. Biol. Rev., 2006, 70(2), 548-563.
[http://dx.doi.org/10.1128/MMBR.00042-05] [PMID: 16760313]
[5]
Dyer, M.D.; Murali, T.M.; Sobral, B.W. Computational prediction of host-pathogen protein-protein interactions. Bioinformatics, 2007, 23(13), i159-i166.
[http://dx.doi.org/10.1093/bioinformatics/btm208] [PMID: 17646292]
[6]
Davis, F.P.; Barkan, D.T.; Eswar, N.; McKerrow, J.H.; Sali, A. Host pathogen protein interactions predicted by comparative modeling. Protein Sci., 2007, 16(12), 2585-2596.
[http://dx.doi.org/10.1110/ps.073228407] [PMID: 17965183]
[7]
Lv, W.; Liu, Z.; Jin, H.; Yu, X.; Zhang, L.; Zhang, L. Three-dimensional structure of HIV-1 VIF constructed by comparative modeling and the function characterization analyzed by molecular dynamics simulation. Org. Biomol. Chem., 2007, 5(4), 617-626.
[http://dx.doi.org/10.1039/b612050d] [PMID: 17285170]
[8]
Tonikian, R.; Zhang, Y.; Sazinsky, S.L.; Currell, B.; Yeh, J.H.; Reva, B.; Held, H.A.; Appleton, B.A.; Evangelista, M.; Wu, Y.; Xin, X.; Chan, A.C.; Seshagiri, S.; Lasky, L.A.; Sander, C.; Boone, C.; Bader, G.D.; Sidhu, S.S. A specificity map for the PDZ domain family. PLoS Biol., 2008, 6(9)e239
[http://dx.doi.org/10.1371/journal.pbio.0060239] [PMID: 18828675]
[9]
Shelton, H.; Harris, M. Hepatitis C virus NS5A protein binds the SH3 domain of the Fyn tyrosine kinase with high affinity: mutagenic analysis of residues within the SH3 domain that contribute to the interaction. Virol. J., 2008, 5, 24.
[http://dx.doi.org/10.1186/1743-422X-5-24] [PMID: 18267011]
[10]
Kadaveru, K.; Vyas, J.; Schiller, M.R. Viral infection and human disease--insights from minimotifs. Front. Biosci., 2008, 13, 6455-6471.
[http://dx.doi.org/10.2741/3166] [PMID: 18508672]
[11]
Frauenfelder, H.; Sligar, S.G.; Wolynes, P.G. The energy landscapes and motions of proteins. Science, 1991, 254(5038), 1598-1603.
[http://dx.doi.org/10.1126/science.1749933] [PMID: 1749933]
[12]
Damaschun, G.; Damaschun, H.; Gast, K.; Zirwer, D. Proteins can adopt totally different folded conformations. J. Mol. Biol., 1999, 291(3), 715-725.
[http://dx.doi.org/10.1006/jmbi.1999.3009] [PMID: 10448049]
[13]
Frauenfelder, H.; McMahon, B. Dynamics and function of proteins: the search for general concepts. Proc. Natl. Acad. Sci. USA, 1998, 95(9), 4795-4797.
[http://dx.doi.org/10.1073/pnas.95.9.4795] [PMID: 9560180]
[14]
Kitao, A.; Go, N. Investigating protein dynamics in collective coordinate space. Curr. Opin. Struct. Biol., 1999, 9(2), 164-169.
[http://dx.doi.org/10.1016/S0959-440X(99)80023-2] [PMID: 10322205]
[15]
Bahar, I.; Erman, B.; Jernigan, R.L.; Atilgan, A.R.; Covell, D.G. Collective motions in HIV-1 reverse transcriptase: examination of flexibility and enzyme function. J. Mol. Biol., 1999, 285(3), 1023-1037.
[http://dx.doi.org/10.1006/jmbi.1998.2371] [PMID: 9887265]
[16]
Bahar, I.; Jernigan, R.L. Cooperative fluctuations and subunit communication in tryptophan synthase. Biochemistry, 1999, 38(12), 3478-3490.
[http://dx.doi.org/10.1021/bi982697v] [PMID: 10090734]
[17]
Hinsen, K.; Thomas, A.; Field, M.J. Analysis of domain motions in large proteins. Proteins, 1999, 34(3), 369-382.
[http://dx.doi.org/10.1002/(SICI)1097-0134(19990215)34:3<369::AID-PROT9>3.0.CO;2-F] [PMID: 10024023]
[18]
Amadei, A.; Linssen, A.B.M.; Berendsen, H.J.C. Essential dynamics of proteins. Proteins, 1993, 17(4), 412-425.
[http://dx.doi.org/10.1002/prot.340170408] [PMID: 8108382]
[19]
van Aalten, D.M.F.; Conn, D.A.; de Groot, B.L.; Berendsen, H.J.C.; Findlay, J.B.C.; Amadei, A. Protein dynamics derived from clusters of crystal structures. Biophys. J., 1997, 73(6), 2891-2896.
[http://dx.doi.org/10.1016/S0006-3495(97)78317-6] [PMID: 9414203]
[20]
Bahar, I.; Atilgan, A.R.; Erman, B. Direct evaluation of thermal fluctuations in proteins using a single-parameter harmonic potential. Fold. Des., 1997, 2(3), 173-181.
[http://dx.doi.org/10.1016/S1359-0278(97)00024-2] [PMID: 9218955]
[21]
Bahar, I.; Atilgan, A.R.; Demirel, M.C.; Erman, B. Vibrational dynamics of folded proteins: significance of slow and fast motions in relation to function and stability. Phys. Rev. Lett., 1998, 80, 2733-2736.
[http://dx.doi.org/10.1103/PhysRevLett.80.2733]
[22]
Atilgan, A.R.; Durell, S.R.; Jernigan, R.L.; Demirel, M.C.; Keskin, O.; Bahar, I. Anisotropy of fluctuation dynamics of proteins with an elastic network model. Biophys. J., 2001, 80(1), 505-515.
[http://dx.doi.org/10.1016/S0006-3495(01)76033-X] [PMID: 11159421]
[23]
Bahar, I.; Jernigan, R.L. Vibrational dynamics of transfer RNAs: comparison of the free and synthetase-bound forms. J. Mol. Biol., 1998, 281(5), 871-884.
[http://dx.doi.org/10.1006/jmbi.1998.1978] [PMID: 9719641]
[24]
Haliloglu, T.; Bahar, I.; Erman, B. Gaussian dynamics of folded proteins. Phys. Rev. Lett., 1997, 79, 3090-3093.
[http://dx.doi.org/10.1103/PhysRevLett.79.3090]
[25]
Tirion, M.M. Large amplitude elastic motions in proteins from a single -parameter, atomic analysis. Phys. Rev. Lett., 1996, 77(9), 1905-1908.
[http://dx.doi.org/10.1103/PhysRevLett.77.1905] [PMID: 10063201]
[26]
Hinsen, K. Analysis of domain motions by approximate normal mode calculations. Proteins, 1998, 33, 417-429.
[http://dx.doi.org/10.1002/(SICI)1097-0134(19981115)33:3<417:AID-PROT10>3.0.CO;2-8]
[27]
Tama, F.; Sanejouand, Y.H. Conformational change of proteins arising from normal mode calculations. Protein Eng., 2001, 14(1), 1-6.
[http://dx.doi.org/10.1093/protein/14.1.1] [PMID: 11287673]
[28]
Zheng, W.; Doniach, S. A comparative study of motor-protein motions by using a simple elastic-network model. Proc. Natl. Acad. Sci. USA, 2003, 100(23), 13253-13258.
[http://dx.doi.org/10.1073/pnas.2235686100] [PMID: 14585932]
[29]
Yang, L.; Song, G.; Jernigan, R.L. How well can we understand large-scale protein motions using normal modes of elastic network models? Biophys. J., 2007, 93(3), 920-929.
[http://dx.doi.org/10.1529/biophysj.106.095927] [PMID: 17483178]
[30]
Flechsig, H.; Popp, D.; Mikhailov, A.S. In silico investigation of conformational motions in superfamily 2 helicase proteins. PLoS One, 2011, 6(7)e21809
[http://dx.doi.org/10.1371/journal.pone.0021809] [PMID: 21829442]
[31]
Hu, G.; Di Paola, L.; Liang, Z.; Giuliani, A. Comparative study of elastic network model and protein contact network fro protein complexes: the hemoglobin case. BioMed Res. Int., 2017.20172483264
[http://dx.doi.org/10.1155/2017/2483264] [PMID: 28243596]
[32]
Dyson, N.; Howley, P.M.; Münger, K.; Harlow, E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science, 1989, 243(4893), 934-937.
[http://dx.doi.org/10.1126/science.2537532] [PMID: 2537532]
[33]
Münger, K.; Werness, B.A.; Dyson, N.; Phelps, W.C.; Harlow, E.; Howley, P.M. Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J., 1989, 8(13), 4099-4105.
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb08594.x] [PMID: 2556261]
[34]
Mirabello, L.; Yeager, M.; Yu, K.; Clifford, G.M.; Xiao, Y.; Zhu, B.; Cullen, M.; Boland, J.F.; Wentzensen, N.; Nelson, C.W.; Raine-Bennett, T.; Chen, Z.; Bass, S.; Song, L.; Yang, Q.; Steinberg, M.; Burdett, L.; Dean, M.; Roberson, D.; Mitchell, J.; Lorey, T.; Franceschi, S.; Castle, P.E.; Walker, J.; Zuna, R.; Kreimer, A.R.; Beachler, D.C.; Hildesheim, A.; Gonzalez, P.; Porras, C.; Burk, R.D.; Schiffman, M. HPV16 E7 Genetic conservation is critical to Carcinogenesis. Cell, 2017, 170(6), 1164-1174.e6.
[http://dx.doi.org/10.1016/j.cell.2017.08.001] [PMID: 28886384]
[35]
Dinkel, H.; Van Roey, K.; Michael, S.; Kumar, M.; Uyar, B.; Altenberg, B.; Milchevskaya, V.; Schneider, M.; Kühn, H.; Behrendt, A.; Dahl, S.L.; Damerell, V.; Diebel, S.; Kalman, S.; Klein, S.; Knudsen, A.C.; Mäder, C.; Merrill, S.; Staudt, A.; Thiel, V.; Welti, L.; Davey, N.E.; Diella, F.; Gibson, T.J. Gibson, 2016. ELM 2016 - data update and new functionality of the eukaryotic linear motif resource. Nucleic Acids Res., 2016, Jan 444(D1), D294-300.
[36]
Zaccai, G. How soft is a protein? A protein dynamics force constant measured by neutron scattering. Science, 2000, 288(5471), 1604-1607.
[http://dx.doi.org/10.1126/science.288.5471.1604] [PMID: 10834833]
[37]
Doruker, P.; Atilgan, A.R.; Bahar, I. Dynamics of proteins predicted by molecular dynamics simulations and analytical approaches: application to α-amylase inhibitor. Proteins , 2000, 40(3), 512-524.
[http://dx.doi.org/10.1002/1097-0134(20000815)40:3<512::AIDPROT180> 3.0.CO;2-M] [PMID: 10861943]
[38]
Pundir, S.; Martin, M.J.; O’Donovan, C. UniProt Protein Knowledgebase. Methods Mol. Biol., 2017, 1558, 41-55.
[http://dx.doi.org/10.1007/978-1-4939-6783-4_2] [PMID: 28150232]
[39]
Ma, J.; Wang, S.; Zhao, F.; Xu, J. 2013, Protein threading using context-specific alignment potential.Bioinformatics (Proceedings of ISMB 2013).Jul 129(13), pp. i257-65.
[http://dx.doi.org/10.1093/bioinformatics/btt210]
[40]
Eyal, E.; Lum, G.; Bahar, I. The anisotropic network model web server at 2015 (ANM 2.0). Bioinformatics, 2015, 31(9), 1487-1489.
[http://dx.doi.org/10.1093/bioinformatics/btu847] [PMID: 25568280]
[41]
Sen, T.Z.; Feng, Y.; Garcia, J.V.; Kloczkowski, A.; Jernigan, R.L. The extent of cooperativity of protein motions observed with elastic network models is similar for atomic and coarser-grained models. J. Chem. Theory Comput., 2006, 2(3), 696-704.
[http://dx.doi.org/10.1021/ct600060d] [PMID: 17710199]
[42]
Liu, X.; Marmorstein, R. Structure of the retinoblastoma protein bound to adenovirus E1A reveals the molecular basis for viral oncoprotein inactivation of a tumor suppressor. Genes Dev., 2007, Nov 121(21), 2711-6.
[http://dx.doi.org/10.1101/gad.1590607]
[43]
Chen, S.C.; Bahar, I. Mining frequent patterns in protein structures: a study of protease families. Bioinformatics, 2004, 20(Suppl. 1), i77-i85.
[http://dx.doi.org/10.1093/bioinformatics/bth912] [PMID: 15262784]
[44]
Nahand, J.S.; Taghizadeh-Boroujeni, S.; Karimzadeh, M.; Borran, S.; Pourhanifeh, M.H.; Moghoofei, M.; Bokharaei-Salim, F.; Karampoor, S.; Jafari, A.; Asemi, Z.; Tbibzadeh, A.; Namdar, A.; Mirzaei, H. microRNAs: New prognostic, diagnostic, and therapeutic biomarkers in cervical cancer. J. Cell. Physiol., 2019, 234(10), 17064-17099.
[http://dx.doi.org/10.1002/jcp.28457] [PMID: 30891784]
[45]
Sadri Nahand, J.; Moghoofei, M.; Salmaninejad, A.; Bahmanpour, Z.; Karimzadeh, M.; Nasiri, M.; Mirzaei, H.R.; Pourhanifeh, M.H.; Bokharaei-Salim, F.; Mirzaei, H.; Hamblin, M.R. Pathogenic role of exosomes and microRNAs in HPV-mediated inflammation and cervical cancer: A review. Int. J. Cancer, 2020, 146(2), 305-320.
[http://dx.doi.org/10.1002/ijc.32688] [PMID: 31566705]
[46]
Shafabakhsh, R.; Reiter, R.J.; Mirzaei, H.; Teymoordash, S.N.; Asemi, Z. Melatonin: A new inhibitor agent for cervical cancer treatment. J. Cell. Physiol., 2019, 234(12), 21670-21682.
[http://dx.doi.org/10.1002/jcp.28865] [PMID: 31131897]
[47]
Brass, A.L.; Dykxhoorn, D.M.; Benita, Y.; Yan, N.; Engelman, A.; Xavier, R.J.; Lieberman, J.; Elledge, S.J. Identification of host proteins required for HIV infection through a functional genomic screen. Science, 2008, 319(5865), 921-926.
[http://dx.doi.org/10.1126/science.1152725] [PMID: 18187620]
[48]
Alberts, I. L.; Todorov, N. P.; Dean, P. M. Receptor flexibility in de novo ligand design and docking. J Med Chem; , 2005, 48, 658 5-6596.

© 2024 Bentham Science Publishers | Privacy Policy